Na+/H+ antiporters are a biologically ubiquitous class of proteins that maintain cell homeostasis by catalyzing the exchange of internal Na+ (or Li+) for external H+. In humans, their dysfunction has been associated with cancer and with cardiac, vascular, gastric, and kidney diseases; in plants, their expression has been correlated with salt resistance; and in bacteria, their activity has been related to virulence. Due to the large number of Na+/H+ antiporters (including at least eleven sub-types in humans), efforts to design drugs for these proteins face the difficult challenge of selectively targeting just one of a number of closel related homologues. This task requires a highly detailed understanding of antiporter structure, function, and energetics; however, Na+/H+ antiporters remain incompletely understood. The mechanisms of alkali and H+ transport are debated; the free energy profiles underlying these processes have not been elucidated; and the dependence of these processes on alkali cation identity and external pH require explanation. Recently, the crystal structure of a bacterial Na+/H+ antiporter, NapA from T. thermophilus, was solved at 3 resolution. In contrast to previous efforts on other Na+/H+ antiporters, the crystal structure was solved in the open (active) form, providing a starting point of unparalleled quality for a detailed theoretical investigation of the mechanism and thermodynamics of antiport. NapA function has been proposed to depend on the coupling between alkali and H+ binding to key active site residues, and large-scale domain motions of more than 10 that alternately expose the binding site to the cell interior and exterior. Therefore, describing the antiport process will require the use of methods that bridge a variety of time and length scales, including coarse-grained models (e.g., elastic network models), enhanced sampling methods (e.g., Markov state models and metadynamics), classical molecular dynamics (MD), reactive MD, and quantum mechanics/molecular mechanics methods. In order to forge connections with experiment, these methods will be applied to study the cation- and pH-dependence of the energetics of antiport for both wild-type NapA and a number of mutants. This work will provide a detailed picture of the antiport process, revealing the role of NapA's important structural elements and its response to various salt and pH conditions, and thereby providing insights into the behavior of a large number of homologous proteins.